ABSTRACT Alcohol and drug abuse are highly prevalent in persons with HIV infection and may contribute to the persistence of HIV Associated Neurocognitive Disorder (HAND) even among those receiving modern antiretroviral treatment. The mechanisms of HAND persistence are not fully understood, but alcohol abuse can increase risk of HAND. We hypothesize that neuroendocrine and immunologic dysregulation occasioned by withdrawal from alcohol can set the stage for HAND not only because severe withdrawal can injure the brain, but also due to disruption of virologic control, and associated systemic and neuroinflammation. The overall aim of this proposal is to determine if alcohol abstinence-induced hypothalamic-pituitary axis (HPA), sympathoadrenalmedullary (SAM), and immune dysregulation acutely (during alcohol withdrawal) disrupt HIV control, and increase likelihood of neurocognitive (NC) impairment; and to determine whether the extent of normalization of HPA and SAM after a further 3 weeks of abstinence relates to improved immune parameters, virologic control and NC functioning. To establish plausibility of this hypothesis we propose to examine 50 alcohol dependent HIV infected persons undergoing inpatient detoxification at the St. Petersburg (Russian Federation) City Addiction Hospital, associated with the Pavlov Medical University at three time points: on admission; at 7 days; and after 28 days, thereby relating the time course of fluctuation in HPA, SAM, immune and virologic markers to intensity of withdrawal symptoms and neurocognitive changes during peak physiologic disturbance, and after resolution of acute withdrawal symptoms. The research brings together a binational team that includes investigators from the UCSD HIV Neurobehavioral Research Program and the Valdman Institute of Pharmacology, Pavlov State Medical University, Saint Petersburg, Russia, with consultation from Dr. George Woody at the University of Pennsylvania. Performing this research in Russia is opportune because: 1) alcohol abuse is a risk factor for both HIV transmission and mortality in Russia and Eastern Europe, hence this work has high global relevance; 2) alcohol detox practice in Russia occurs in an in-patient hospital setting rather than the more typical outpatient or brief stay detox settings in the US. This makes it feasible to study effects of withdrawal on HIV control longitudinally in a clinical setting. If proof of principle is supported, our findings can lead to more mature research on effects of instituting antiretroviral treatment and pharmacologic and behavioral interventions to prevent relapse and reduce likelihood of neurotoxic events during detoxification in HIV+ persons, and to altered practice guidelines for the management of HIV infected persons at risk for undergoing alcohol withdrawal. !